Abstract As the general population ages, understanding the factors that contribute to longevity, healthy aging, and disability is paramount. Sex hormones (SH) have been hypothesized to be one of the possible reasons for the gender difference in both longevity and neurodegenerative disorders (ND).13 SH, specifically estrogen, progesterone and testosterone) have shown neuroprotective effects in animal and cell-line studies,14?16 and in disease-related animal models for Alzheimer?s Disease,17?24 Parkinson?s Disease,25?29 and Huntington?s Disease.30?35 Previous studies analyzing the effect of sex hormones (reproductive history or hormone metabolizing genes) on ND and longevity in human observational studies have been inconclusive. 36?104 Also inconsistent have been the clinical trials that analyzed whether postmenopausal hormone therapy had a positive effect on ND.105?113 Hence, the role of SH on longevity and ND remain elusive. The goal of this project is to analyze the association between sex hormones and epigenetic aging and age- related neurodegenerative diseases. The project is divided into three aims. In the first aim, three different methods to predict SH levels will be created using whole genome genetics, large-scale methylation data, and questionnaire-based information. In the second aim, both measured SH and SH predictive scores will be associated with epigenetic age. Epigenetic age is known to be strongly associated with mortality and therefore, is a robust measure to estimate longevity.114,115 In the third aim, the development of ND (Alzheimer?s disease and Parkinson?s disease), as well as age of onset (Alzheimer?s disease, Parkinson?s disease and Huntington?s disease), will be associated with the SH predictive scores based on the first aim. Finally, assuming an association was identified in aims 2 and 3, mediation analysis will be performed as a potential sub-aim to analyze whether epigenetic aging can partially explain the association between sex hormones and ND. To ensure statistical power and the ability to verify and replicate the findings, several large observational datasets will be used. These studies and approaches will address the role of sex hormones from various angles, and will help to triangulate evidence and inform future research into potential therapeutic targets. With training from, and collaborations with several experts in genetic, epigenetic, and epidemiological analyses, the applicant will gain expertise to unlock some of these questions and contribute to aging and neurodegenerative disease-related discoveries. Maximizing an interdisciplinary approach, incorporating genetics, epigenetics, epidemiology, biostatistics and neurology considerations, will generate a broad range of independent research.